physical activity and colorectal cancer...

Physical Activity, Energy Balance and Colorectal Cancer Survivorship

Jeffrey Meyerhardt, MD, MPH

Dana-Farber Cancer Institute

Disclosures

• None

Colorectal Cancer Epidemiology

• Estimated 136,830 new cases in 2014 • Fourth most common cancer in the United

States • Third most commonly diagnosed cancer in men • Third most commonly diagnosed cancer in women

• Estimated 50,310 deaths from CRC in 2014 –Second leading cause of cancer deaths in the

United States

Siegel R et al. Ca Cancer J Clin. 2014;63:9–29.

Colorectal Cancer:

Risk Factors Overview

Decrease Risk Increase Risk Uncertain Impact

Screening Family history Statins

Exercise

Aspirin / NSAIDs

Ulcerative colitis/

Crohn’s Disease

Fiber

Glycemic load

Vitamin D Diabetes Fruits/Vegetables

Post-menopausal

estrogen

Obesity

Red meat

Folic Acid

Calcium Western diet

Alcohol

Smoking

Energy Balance

Calorie Intake

Modified by ingestion and/or

absorption (e.g., changes in

microflora, surgery,

pharmacologic agents)

Resting Metabolic Rate

Energy needed to maintain body function at rest. Accounts for ~60-75% of expenditure. Modified by

lean body mass (age), and external/internal temperature.

Physical Activity

Energy needed for activity.

Usually accounts for 15-30%

of expenditure, but most

modifiable component

Thermic Effect of Food

Energy needed for digestion or metabolism. Accounts for <10%

of expenditure. Modified somewhat by digestibility,

capsaicin, caffeine.

Body Weight

Gain

Stable

Loss

Energy Intake

(energy in)

Total Energy Expenditure

(energy out)

From Demark-Wahnefried et. al. Cancer Epidemiol Biomarkers Prev. 2012 Aug;21(8):1244-59.,

Physical Activity and Colon Cancer Risk

Boyle T et al. JNCI J Natl Cancer Inst 2012;104:1548-1561

Relative risk of colon cancer per 5-unit

increase in BMI (in kg/m2)

Larsson S C , and Wolk A Am J Clin Nutr 2007;86:556-565

Meta-analysis of red and processed meats

consumption and the risk of colorectal cancer

Chan DSM, Lau R, Aune D, Vieira R, et al. (2011) Red and Processed Meat and Colorectal Cancer Incidence: Meta-Analysis of

Prospective Studies. PLoS ONE 6(6): e20456.

What about Cancer Patients/Survivors

Adherence to Lifestyle Behavior Recommendations in Colorectal Cancer

Patients/Survivors • 9,105 survivors of 6 difference cancers (1,918

CRC) within 10 years of diagnosis

Cancer Group Physical

Activity * (%) 5 fruit/vege-

A-Day (%) Smoking

cessation (%)

Breast 37.1 18.2 88.1

Prostate 43.2 15.6 91.6

Colorectal 35.0 15.9 91.3

Bladder 36.0 16.3 82.6

Uterine 29.6 19.1 91.1

Skin melanoma

47.3 14.8 89.0

JCO May 1, 2008 vol. 26 no. 13 2198-2204

* at least 150 minutes of moderate-to-strenuous or 60 minutes of strenuous PA per week

Trajectory of Cancer Survivorship

• Active Treatment and Recovery

• Living after recovery, including disease-free and stable disease

• Advanced cancer and end of life

CA: A Cancer Journal for Clinicians; 62: 242-274, July / August 2012

Physical Activity Immediately After Surgery

Int J Colorectal Dis. 2013 May;28(5):643-51 StretchingCore Resistance Ambulation

Physical Activity Immediately After Surgery

Int J Colorectal Dis. 2013 May;28(5):643-51

Exercise group Usual care

p value Effect size Median (IQR)

Mean (SD) Median (IQR)

Mean (SD)

Time to flatus (h)

50.9 (38.6–64.4)

52.2 ± 21.6 73.87 (47.5–95.8)

71.9 ± 29.2 0.036 0.68

Time to liquid diet intake (h)

69.8 (64.9-91.7)

76.9 ± 24.4 86.74 (80.7–100.0)

86.0 ± 20.7 0.177 0.44

Role of Physical Activity during Active Treatment and Recovery

• Numerous studies have examined association of physical activity to quality of life and overall health

• 9 published physical activity only intervention trials and 2 multiple behavioral intervention trials published – Timing of initiation varied

– Type of intervention varied

– Several trials with multiple cancer types

Randomized Study of Exercise v Usual Care in Colorectal Cancer Survivors

Personalized Exercise Counseling v Usual care 16 weeks

Most on adjuvant therapy

Eur J Cancer Care (Engl). 2003 Dec;12(4):347-57. 3


Adherence in exercise group – 25%; Contamination in control group – 50%

Control Group (n=31) Exercise Group (n=62) P

Mild exercise 56.53 (65.18) 43.30 (103.41) 0.518

Moderate exercise 116.21(181.50) 145.24 (106.50) 0.334

Strenuous exercise 7.38 (36.33) 4.99 (20.23) 0.684

Moderate/strenuous exercise combined

123.59 (182.73) 150.23 (109.67) 0.383

Total exercise 180.12 (185.82) 193.52 (146.36) 0.705

% > 60 Moderate/strenuous exercise

51.6 75.8 0.019

% > 150 Moderate/strenuous exercise

32.3 41.9 0.366




Adherence in exercise group – 25%; Contamination in control group – 50%

Variable Baseline P-value Post-intervention

Mean change D in mean change [95% CI]

P-value

Intent-to-Intent

FACT-C (0–132)

Exercise group

106.0 (14.0) 107.4 (16.5) 1.4 (15.7)

Control group 107.0 (16.0) 0.756 109.8 (18.8) 2.7 (12.5) −1.3 [−7.8 - 5.1]

0.679

Ancillary Analyses

Increased fitness group

106.9 (15.6) 110.9 (14.9) 4.3 (13.2)

Decreased fitness group

105.9 (13.0) 0.796 103.7 (19.8) −2.2 (16.1) 6.5 [0.4 - 12.6]

0.038

Role of Physical Activity during Active Treatment and Recovery

• Among exercise only intervention trials mix of outcomes – Backman et al – no effect on HRQOL, anthropometry

or biomarkers for 10 week intervention of daily 10,000 steps and weekly group walks

– Lin et al – improved strength, fitness, physical function, social function, fatigue and pain but none statistically significant in 12 week aerobic and resistance supervised sessions

– Cheville et al – improved mobility, fatigue and sleep quality with home based program

Acta Oncol. 2014 Apr;53(4):510-20; Cancer Nurs. 2014 Mar-Apr;37(2):E21-9; J Pain Symptom Manage. 2013 May;45(5):811-21

Trajectory of Cancer Survivorship





Role of Physical Activity during Living after Recovery Phase

• Multiple exercise only studies with mixed results

– Pinto et al used telephone based intervention - but no intervention effect on fatigue, physical function, or QOL

– Ligibel et al used telephone based intervention – improvement in fitness and physical function

Psychooncology. 2013 Jan;22(1):54-64; Breast Cancer Res Treat. 2012 Feb;132(1):205-13.


• 2 multiple behavioral change studies

– CanChange (CRC within 12 months) - telephone based intervention focusing on physical activity, weight management, dietary habits, alcohol, and smoking

• ↑PA, ↓BMI, ↓Energy from total fat, ↑Vegetable intake

• No significant difference in QOL, fatigue

– RENEW (elderly > 5 yrs from dx – prostate, breast, CRC) - telephone based intervention focusing on physical activity, moderate weight loss and improved diet quality

• Reduced rate of self report functional decline

J Clin Oncol. 2013 Jun 20;31(18):2313-21; JAMA. 2009 May 13;301(18):1883-91.


• Physical activity and risk of recurrence

– Data from prospective cohort study

– Studies vary on timing of physical activity measurement (before or after diagnosis)

– Intervention studies have focused on potential biomarkers

Physical Activity and

Colorectal Cancer Specific Survival

• Cohort study from Australia of 526 colorectal cancer patients

with pre-diagnosis physical activity assessment

Colorectal cancer specific survival

Gut. 2006 Jan;55(1):62-7

CALGB 89803

• NCI-sponsored adjuvant therapy trial for stage III colon cancer

• Patients randomized to Roswell Park 5-FU/LV or IFL (bolus 5-

FU/LV/Irinotecan)

• 1264 enrolled between 1999 and 2001

Patients enroll on adjuvant therapy trial

0 2 4 6 8 10 12 14 16

chemotherapy

Complete questionnaire

Complete questionnaire

every 3 month f/u

J Clin Oncol; 25:3456-3461 2007

CALGB 89803

J Clin Oncol. 2007 Aug 10;25(23):3456-61.

89803 and Exercise: Disease-Free Survival

in Stage III Colon Cancer Survivors

J Clin Oncol; 24:3535-3541 2006

Regular Physical Activity (met-hours per week)

Haz

ard

Rat

io R

ecu

rre

nce

or

De

ath

89803 and Exercise: Disease Free Survival

J Clin Oncol; 24:3535-3541 2006

89803 and Exercise: Stratification

J Clin Oncol; 24:3535-3541 2006

Statistical Considerations

• Reverse causality

– Is the exposure changing outcomes or the outcome changing exposure

– Restrict to events at least 90 days from exposure

– Sensitivity analyses to extend restriction to 6 months and 12 months

• Recall bias

– The clock starts at time of questionnaire completion – all events are prospective beyond the exposure data

– Limits generalizability – data speak to those that get to point of questionnaire

NHS and Post-diagnosis Physical Activity

J Clin Oncol; 24:3527-3534 2006

NHS and Pre-diagnosis Physical Activity

J Clin Oncol; 24:3527-3534 2006

NHS and Change in Physical Activity

J Clin Oncol; 24:3527-3534 2006

Meta-Analysis of Pre-Diagnosis Physical

Activity and Colorectal Cancer Outcomes

Int J Cancer. 2013 Oct 15;133(8):1905-13.

Meta-Analysis of Post-Diagnosis Physical

Activity and Colorectal Cancer Outcomes

Int J Cancer. 2013 Oct 15;133(8):1905-13.

CHALLENGE: Colon Health and Life-Long Exercise Change trial

High risk Stage II or stage III colon cancer - completed adjuvant chemotherapy within 2-6 months

REGISTRATION

Baseline Testing

STRATIFICATION Disease stage high risk III; centre; BMI ≤ 27.5 vs. > 27.5;

ECOG PS 0 vs. 1

RANDOMIZATION

ARM 1 Physical Activity Program + General Good Health

Education Material (Intervention Arm)

ARM 2 General Health Education Materials

(Control Arm)

Assessment of disease-free survival every 6 months for first 3 years and annually from years 4-10

Courneya Curr Oncol.2008 Dec;15(6):271-8.

Lee, Meyerhardt, Giovannucci, Jeon, PLOS One, In Press

Body Mass Index and Stage I-III

Colorectal Cancer

CALGB 89803: DFS By Dietary Pattern

1 1 1.1 1 0.7

1.3

0

0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5 Quintiles of Dietary Pattern H

azar

d R

atio

fo

r C

ance

r R

ecu

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r D

eath

Prudent diet

1.2

2 2.2

3.9

Western diet

P, trend < 0.001

Meyerhardt, J. et al. JAMA 2007298(7):754-764.

CALGB 89803: Dietary Pattern

Meyerhardt, J. et al. JAMA 2007;298:2263-a.

Dietary Patterns

• Study of 529 colorectal cancer patients in Newfoundland

• Pre-diagnosis diet

Zhu et al BMJ Open 2013 Feb 7;3(2).

DFS – CRC Colon Rectal

Glycemic Load

in Colon Cancer Patients

Quintiles of Glycemic Load Haz

ard

Rat

io f

or

Can

cer

Rec

urr

ence

or

Dea

th

Meyerhardt, J. et al JNCI 2012

Glycemic Load


Quintiles of Glycemic Load Haz

ard

Rat

io f

or

Can

cer

Rec

urr

ence

or

Dea

th

Meyerhardt, J. et al JNCI 2012

1

0.650.81

10.91

1 0.991.07

1.7

2.26

0

0.5

1

1.5

2

2.5

1 2 3 4 5

BMI < 25

BMI > 25

Sugar Sweetened Beverage


Sugar Sweetened Beverage Intake

Haz

ard

Rat

io f

or

Can

cer

R

ecu

rren

ce o

r D

eath

Fuchs MA et al, PLOS One 2014

P trend = 0.03

Insulin-related Growth Factors

and Outcomes

JCO 2009;27:176-185

C-peptide IGFBP-1

Colorectal cancer-specific survival (years) Colorectal cancer-specific survival (years)

Overall survival (years) Overall survival (years)

All stage I-III cases with nuclear CTNNB1(+)

All stage I-III cases with nuclear CTNNB1(-)

Log-rank p=0.0054

Log-rank p=0.029

Log-rank p=0.73

Log-rank p=0.60

A C

B D

Even

t p

rob

abili

ty

Even

t p

rob

abili

ty

Even

t p

rob

abili

ty

Even

t p

rob

abili

ty

≥18 MET-hours/w

<18 MET-hours/w

≥18 MET-hours/w

<18 MET-hours/w

≥18 MET- hours/w

<18 MET- hours/w

≥18 MET-hours/w

<18 MET-hours/w

Association between Physical Activity and Outcomes by CTNNB1 (b catenin) Status

JAMA. 2011 Apr 27;305(16):1685-94

WNT-CTNNB1 signaling adipogenesis, obesity, and metabolic diseases.

Inactive WNT-CTNNB1 signaling pathway associated with energy balance Active WNT-CTNNB1 signaling pathway independent of energy balance

Cancer Epidemiol Biomarkers Prev 2013;22:1142-1152

Association between Physical Activity and Outcomes by PTGS2 (COX-2) Status

TGS2 and its enzymatic product, PGE2, inflammatory responses and associated with colorectal cancer development and progression Physical activity modulate PGE2 synthesis

Role of Physical Activity in Advanced Cancer and End of Life Phase





Role of Physical Activity in Advanced Cancer and End of Life Phase

• Limited data on impact of physical activity in advanced disease patients in terms of quality of life and tolerance to chemotherapy

• Jeon et al – CALGB 89803 – for those patients that recurred, increased physical activity associated with nonsignficant improved survival (Hazard ratio 0.71 (95% CI, 0.46-1.11); P trend = 0.052)

J Support Oncol. 2009 Jan-Feb;7(1):27-34; Clin Colorectal Cancer. 2013 Dec;12(4):233-8.

Conclusions

• Emerging data of association/impact of physical activity and other energy balance factors across the colorectal cancer continuum

• Many unanswered question

– Timing of initiation of therapy

– Length of intervention – lifelong versus more critical in peri-diagnosis phase

– Level of physical activity and what diet necessary for benefit

– Best approach to use to study – supervised, remote

– Secondary gains (other comorbidities, other cancers)

physical activity and colorectal cancer...

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